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P A Colley

Publications and source records attributed to P A Colley.

11 recordsLinked to original sources
PubMed2001

The use of antibody engineering to create novel drugs that target N-methyl-D-aspartate receptors.

According to a recent World Health Organization survey, there are over four hundred million people worldwide suffering from mental and neurological disorders; schizophrenia affects some forty-five million people, and unipolar major depression ranked fifth in major causes of disability and death. Clearly it is of the utmost importance to develop new, effective, and safe neuro-pharmaceuticals with this increasing "global burden of disease". To this end, we have developed a strategy of generating monoclonal antibodies that act as modulators of the cell-surface central nervous system receptor-ion channel complexes. In this review we will focus on the generation and characterization of a monoclonal antibody that acts as a partial agonist to the N-methyl-D-aspartate receptor. The creation of peptide mimetics, derived from this monoclonal antibody, that may be useful as cognitive enhancers and protect neurons hypoxic and ischemic insults caused by stroke, will also be discussed.

Amino Acid Sequence↗
PubMed1997

Metabotropic glutamate receptor mediated long-term depression in developing hippocampus.

The effects of bath application of the metabotropic glutamate receptor (mGluR) agonist 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD, 10 microM) were studied at the Schaffer collateral-CA1 synapse in hippocampal slices from rats of 8-33 days postnatal age. In immature animals (8-12 days) ACPD induced a biphasic response characterized by an acute decrease in field EPSP slope (approximately 50-60% of baseline) in the presence of the agonist, followed by long-term depression (LTD, approximately 75-80% of baseline) after washout. In animals older than 20 days, ACPD induced a slow onset potentiation or minimal change. Both the acute depression and LTD were blocked by the mGluR antagonist alpha-methyl-4-carboxyphenyl glycine (MCPG). ACPD-induced LTD was blocked by the N-methyl-D-aspartate receptor (NMDAR) antagonists D(-)-2-amino-5 phosphopentanoic acid (AP5) and dizocilpine maleate (MK-801), and by ethanol. Glutamic pyruvic transaminase, an enzyme that selectively metabolizes endogenous extracellular glutamate, also blocked LTD suggesting that the requisite NMDA currents were tonically activated by extracellular rather than synaptically released glutamate. ACPD-induced LTD was blocked by staurosporine, indicating a requirement for serinethreonine kinase activation, and was unaffected by the L-type voltage sensitive calcium channel blocker nitrendipine and the A1 adenosine receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT). Because mGluR-mediated LTD was observed only in immature CA1, mGluRs may play a role in hippocampal development, perhaps by contributing to synapse pruning in a temporally restricted fashion.

Animals↗
PubMed1995

AP5 blocks LTP in developing rat dentate gyrus and unmasks LTD.

The hippocampal dentate gyrus undergoes active neuronogenesis as well as growth and regression of neuronal elements and connections during the early postnatal period. In some brain regions, most notably in the visual system, both activity-dependent synaptic plasticity and NMDA receptor activation are candidate mechanisms by which neuronal architecture may be refined during brain maturation. To investigate whether similar mechanisms might obtain in developing dentate, we studied the effects of tetanic stimulation before and after NMDA receptor blockade in hippocampal slices from rats at 7-33 days. Field potentials were recorded in the suprapyramidal granule cell layer in response to stimulation of the medial perforant path. Robust long-term potentiation (LTP) of population spike amplitude (approximately 200% of baseline) was produced by a single tetanus (100 Hz, 2 s, 200 microseconds) at all ages studied. Application of 10 microM AP5 depressed population spike amplitude only in the younger slices (approximately 81% of baseline at 8-15 days; approximately 86% of baseline at 16-24 days), suggesting that the NMDA receptor-mediated component of normal synaptic transmission is higher in early development and decreases with maturation. AP5 prevented or significantly diminished LTP at all ages, establishing the NMDA dependence of LTP induction in the medial perforant path throughout development. AP5 also unmasked tetanus-induced homosynaptic long-term depression (62-75% of baseline) in the younger slices (8-24 days). Thus, prominent NMDA receptor-mediated activity and the capacity for bidirectional synaptic plasticity are characteristic of immature dentate. These processes may influence dentate morphogenesis by contributing to the growth, regression, and stabilization of neuronal elements.

2-Amino-5-phosphonovalerate↗
PubMed1994

Perforant path kindling alters dentate gyrus field potentials and paired pulse depression in an age-dependent manner.

The effects of rapid perforant path kindling on field potentials and paired pulse depression were studied in the dentate gyrus of rats at four developmental stages: 14-16 days, 20-22 days, 27-29 days and 40-60 days (adult). In rats 14-29 days kindling was associated with sustained potentiation of population spike amplitude and population EPSP slope; in adults a progressive decline was seen in both measures. Inhibitory circuitry as assessed by paired pulse depression was intact at all ages studied. Kindling produced no lasting changes in this measure at 14-22 days; in the older age groups a significant increase in paired pulse depression was seen. Thus immature animals differed from adults in that they manifested persistent facilitation of excitatory transmission as a result of kindling and failed to mount a compensatory inhibitory response. These results suggest that the balance between excitation and inhibition is more readily shifted toward excitation in immature animals in a manner that may contribute to their unique vulnerability to epileptogenesis.

Aging↗
PubMed1992

Postsynaptic then presynaptic protein kinase C activity may be necessary for long-term potentiation.

Protein kinase C inhibitor was injected intracellularly by iontophoresis into CA1 somata either before or after long-term potentiation in the hippocampal slice preparation. Two different protein kinase C inhibitors, polymyxin B (PMXB) or 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7), injected 10 min before long-term potentiation induction caused potentiated responses to return to baseline 15-35 min after induction without significantly affecting the initial magnitude of potentiation. There was no effect on long-term potentiation persistence when H-7 or PMXB was injected intracellularly 5 min after long-term potentiation induction. In contrast, focal extracellular micro-pressure ejection of protein kinase C inhibitor in the stratum radiatum, 15 or 30 min, but not 60 min after long-term potentiation induction caused decay of long-term potentiation to baseline. This is probably a presynaptic action since intracellular inhibitors injected postsynaptically were ineffective 5 min after long-term potentiation induction. Focal application to stratum pyramidale produced a weaker decay than to stratum radiatum suggesting a Schaffer collateral presynaptic terminal site of action. We propose that activation of postsynaptic protein kinase C activity is necessary for long-term potentiation persistence but this activity persists for less than 5 min after induction. Presynaptic protein kinase C activity is also necessary for persistence and is time-limited to less than 60 min. It is attractive to think that these two events are sequentially activated and employ different protein kinase C subtypes differentially localized to presynaptic or postsynaptic elements.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1990

Inhibition of protein kinase C blocks two components of LTP persistence, leaving initial potentiation intact.

Protein kinase C (PKC) activity is increased following hippocampal long-term potentiation (LTP; Akers et al., 1986). A similar increase in PKC activity is measured following the induction of a long-lasting potentiation with abbreviated high-frequency stimulation (HFS) in combination with PKC-activating phorbol esters (Colley et al., 1989). Because phorbol esters have no effect on the initial potentiation produced with HFS, and because PKC activity appears to be related to the persistence of LTP and not to the initial change, we concluded that PKC regulates a post-initiation component of LTP. To define the time domain in which PKC activation is necessary for LTP, we studied the effect of the PKC inhibitors polymyxin B (PMXB) and 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7) micropressure ejected at different time points before and after the induction of LTP. LTP was produced in intact rats with HFS of the perforant path, and inhibitor ejections were made in the molecular layer of the dentate gyrus. PMXB, which at lower doses is a selective inhibitor of PKC, had no effect on initial potentiation, yet caused decay of the potentiated response to baseline within 2 hr. Decay occurred when PMXB was ejected 15 min before and 15 and 30 min after HFS. PMXB, at either low or high doses, was ineffective in blocking LTP persistence at time points greater than 30 min after HFS. Low doses of H-7 produced similar effects to those of PMXB. However, in contrast to a high dose of PMXB, a high dose of H-7 inhibited the persistence of LTP when delivered 240 min after HFS.(ABSTRACT TRUNCATED AT 250 WORDS)

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1989

Dose-dependent phorbol ester facilitation or blockade of hippocampal long-term potentiation: relation to membrane/cytosol distribution of protein kinase C activity.

We have proposed that the translocation/activation of protein kinase C (PKC) in synergism with a Ca2+-mediated event plays an essential role in hippocampal long-term potentiation (LTP). In a previous study, we saw no effect of PKC-activating phorbol esters alone on baseline responses, although it has been reported by others to enhance synaptic transmission. To resolve this discrepancy, we investigated the dose-response to phorbol esters of both baseline and potentiated granule cell responses elicited with perforant path stimulation. It was confirmed that iontophoretic ejection of phorbol ester to the dentate hilus, which alone had no effect on baseline responses, prolonged the persistence of potentiation produced by 2 trains of 400 Hz stimulation. These data support the proposed synergistic model in which the effects of phorbol ester and high frequency stimulation together produce a long-lasting potentiation of synaptic activation. A similar synergism was observed with ejection of a lower dose of phorbol ester into the perforant path synaptic zone in the molecular layer. Higher doses delivered to the synaptic zone without 400 Hz stimulation were sufficient to enhance baseline synaptic responses, but these doses inhibited the initial potentiation induced with 2 trains of 400 Hz stimulation delivered immediately after ejection. There was at times a slowly developing enhancement observed after the initial blockade. Thus, induction of a persistent synaptic enhancement was observed without initial potentiation. Measurement of PKC activity in membrane and cytosol indicated that PKC activation is only associated with the persistence phase of LTP. In contrast, there was no change in PKC subcellular distribution associated with the blockade of initial potentiation by higher doses of PDBu.

Animals↗
PubMed1986

Direct relation of long-term synaptic potentiation to phosphorylation of membrane protein F1, a substrate for membrane protein kinase C.

One hour after long-term potentiation (LTP) in the intact hippocampus, a selective increase in protein F1 in vitro phosphorylation was observed in homogenate prepared from dorsal hippocampus. Protein F1 phosphorylation was directly related to the magnitude and persistence of potentiation. No other phosphoprotein studied exhibited a relationship with synaptic enhancement. Low-frequency, non-potentiating stimulation did not increase protein F1 phosphorylation, and phosphorylation of F1 was not elevated when high-frequency stimulation did not produce potentiation. We also confirmed our earlier demonstration of a similar pattern of results 5 min after LTP. In related work we have previously observed: that protein F1 is a substrate for protein kinase C (PKC); that membrane PKC activity was increased by translocation from the cytosol following LTP; and that membrane PKC activity was directly related to the persistence of enhancement. We therefore predicted in the present study that protein F1 phosphorylation in a dorsal hippocampal membrane fraction would be related to LTP. Hippocampal membrane protein F1 was found to be directly related to both the magnitude and persistence of response enhancement. Thus the molecular events leading to prolonged potentiation may involve increased PKC/protein F1 association. Persistence of potentiation may be related to synaptic growth processes involving the growth-associated function of protein F1.

Animals↗
PubMed1986

Translocation of protein kinase C activity may mediate hippocampal long-term potentiation.

Protein kinase C activity in rat hippocampal membranes and cytosol was determined 1 minute and 1 hour after induction of the synaptic plasticity of long-term potentiation. At 1 hour after long-term potentiation, but not at 1 minute, protein kinase C activity was increased twofold in membranes and decreased proportionately in cytosol, suggesting translocation of the activity. This time-dependent redistribution of enzyme activity was directly related to the persistence of synaptic plasticity, suggesting a novel mechanism regulating the strength of synaptic transmission.

Animals↗
PubMedDate not supplied

Long-term potentiation as synaptic dialogue.

We have proposed a testable model of the physiological and biochemical events underlying LTP that offers the following novel features. (1) The focus is not on a single mechanism or synaptic site, but rather on the integration and interaction of mechanisms occurring on both sides of the synapse, (2) beta PKC plays a critical presynaptic role in LTP, while gamma PKC functions postsynaptically. (3) These stages can be ordered in a time-delimited sequence of post- then presynaptic molecular events based on the period of effectiveness of inhibitor compounds. (4) The distinction is made between the time when kinase activation occurs and the time when the potentiated response requiring this kinase activation is observed.

Animals↗